doi: 10.1161/hy1101.092967
(Hypertension. 2001;38:1054.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Genetic and Environmental Determinants of Plasma Nitrogen Oxides and Risk of Ischemic Heart Disease
From the Centre for Cardiovascular Genetics (N.J., L.C.J., S.E.H.) and Centre for Clinical Pharmacology (N.J., L.C.J., P.V., A.D.H.), University College London Medical School, Rayne Institute; and MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine (S.B., J.A.C., G.J.M.), London, UK. Dr Bujac is currently at Sandwich Laboratories, Pfizer Ltd, Sandwich, Kent CT13 9NJ, UK.
Correspondence to Aroon Hingorani, Centre for Clinical Pharmacology, UCL, Rayne Institute, London WC1E 6JJ, UK. E-mail a.hingorani{at}ucl.ac.uk
Abstract—— Endothelial dysfunction, caused in part by reduced NO bioavailability, is a feature of hypercholesterolemia, hypertension, smoking, and atherosclerosis. We examined whether cholesterol, blood pressure, smoking status, and polymorphisms in the endothelial NO synthase gene (NOS 3) influence NO production (as assessed by the plasma levels of nitrogen oxides, NOx) in middle-aged men. We also determined whether plasma NOx or NOS 3 genotype predicted the risk of is chemic heart disease (IHD). We studied 3052 men who were initially free of IHD and recruited from 9 UK primary care practices. Blood pressure, age, body mass index, serum cholesterol, and smoking status were assessed at baseline and annually over 8.1 years of follow-up, and all IHD events were recorded. DNA samples were screened for 4 NOS 3 gene polymorphisms: -786 T/C, -922 A/G, 894 G/T (which predicts a Glu298
Asp amino acid substitution in the mature protein), and a 27-bp tandem repeat in intron 4 (eNOS4a/4b). NOx was measured in plasma samples obtained on entry in 1121 participants from North Mymms and Chesterfield general practices, together with an additional 571 recruits selected at random. Genotype frequencies were in Hardy-Weinberg equilibrium, and linkage disequilibrium was detected between all the NOS 3 polymorphismsstudied, with the strongest allelic association being detected between -922 A/G and -786 T/C polymorphisms in the gene promoter (
=0.90, P<0.001). Plasma NOx was lower in smokers than in nonsmokers in the North Mymms (10.8±4.5 versus 11.8±4.6 µmol/L, P=0.13), Chesterfield (8.4±3.6 versus 9.9±4.0 µmol/L, P=0.01), and random samples (10.7±5.1 versus 11.7±4.7 µmol/L, P=0.03). A weak but significant inverse relationship was detected between plasma NOx and serum cholesterol only in the North Mymms data set (r=-0.14, P=0.02). No relationship was detected between plasma NOx and any of the NOS 3 polymorphisms, nor was there any association between any NOS 3 polymorphism and risk of an IHD event in either smokers or nonsmokers. These data support the hypothesis that the endothelial dysfunction observed in the blood vessels of smokers is related to reduced NO bioactivity but indicate that NOS 3 genotype does not influence significantly the level of plasma NOx or the risk of IHD in this population sample of middle-aged British men.
Key Words: endothelium • nitricoxide • polymorphism • endothelial dysfunction • smoking
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